The principal purpose of the proposed chemical research program is the synthesis of novel bifunctional metal chelation reagents based upon both new and old chemical concepts and directed toward the complexation of the specific radiometal ions 111In+3, 90Y+3 and 67Cu+2 followed by their subsequent conjugation to MAbs. The resulting radiolabeled MAbs would then be evaluated for applications in tumor imaging (111In+3) and beta-therapy (90Y+3 and 67Cu+2). It is recognized that these three radiometal ions differ in chemical properties as well as ionic radii and preferred modes of coordination to ligands. Consequently, the bifunctional chelation reagents chosen for synthesis and evaluation are designed to elaborate upon the bonding characteristics unique to each of the three metal ions of interest and thus maximize the stabilities of their chelates in vivo. Initial synthesis work will involve the development of routes to modified DTPA bifunctional chelate reagents which will contain lengthened carbon chains between amino nitrogen centers to enhance chain flexibility. In addition, chain-branching at the central nitrogen atom of DTPA will be examined as a means to increased functionality. The synthesis of a series of cyclic polyaminocarboxylic acid derivatives which will adopt aza crown conformations will be carried out. By varying the size of the aza crown macrocycle backbone of these species, it should be possible to obtain ligands which bind tightly to a specific metal ion having proper ionic radius such as 111In+3 or 90Y+3 through essentially ion-dipole interactions and/or weak covalent bonding (111In+3). A newly discovered class of pi-bonding chelates specific for transition metals such as 67Cu+2 will be further developed for conjugation to proteins. These pi-bonded species are easily prepared at high pH in aqueous media. The bifunctional chelate systems presented above will be coupled to MAb fragments using a linker molecule capable of binding at least ten chelate units to itself and then binding to the thiol function of a desired antibody fragment using known methods.